A Chronobiologic Approach to Ethanol and Acidified Aspirin Injury of the Gastric Mucosa in the Rat

Several models of erosive peptic disease have used drug-induced lesions to examine protective mechanisms of the gastric mucosa. Physiological processes such as acid secretion, motility, or epithelial cell turnover have circadian rhythms which may modulate the susceptibility of the gastric mucosa to injury. In this review are described recent studies which demonstrated that susceptibility to gastric mucosal injury by acidified aspirin and absolute ethanol varied with the phases of the light-dark cycle. Acidified aspirin caused significantly more gastric mucosal lesions when administered early in the light phase compared to administration early in the dark phase. The differences in susceptibility were not altered by pretreatment conditions such as immobilization or length of the fasting period. Absolute ethanol also caused significantly greater gastric mucosal injury when administered in the light than in the dark phase, but this difference was only evident in rats immobilized during the pretreatment fasting period. Further studies are needed to correlate circadian susceptibility to drug-induced gastric mucosal injury with physiological defense mechanisms. Careful attention to circadian timekeeping may allow us to refine therapy to optimize physiological defense mechanisms in the stomach.     

高效液相法测定阿司匹林肠溶片中阿司匹林含量

建立阿司匹林片HPLC含量测定方法。采用Kromasil（C18 150mm×4．6mm,5u）色谱柱,以乙腈-四氢呋喃-冰醋酸-水（23：5：5：61）为流动相;检测波长为280nm;流速1．0mL／min;进样量20uL,柱温：室温。阿司匹林在12．5～250ug／mL范围内有良好的线性关系。平均回收率100.22％,RSD为1．2％。本法操作简便、快速、结果准确、专属性强。     

Aspirin and cancer: biological mechanisms and clinical outcomes

Evidence on aspirin and cancer comes from two main sources: (1) the effect of aspirin upon biological mechanisms in cancer, and (2) clinical studies of patients with cancer, some of whom take aspirin. A series of systematic literature searches identified published reports relevant to these two sources. The effects of aspirin upon biological mechanisms involved in cancer initiation and growth appear to generate reasonable expectations of effects upon the progress and mortality of cancer. Clinical evidence on aspirin appears overall to be favourable to the use of aspirin, but evidence from randomized trials is limited, and inconsistent. The main body of evidence comes from meta-analyses of observational studies of patients with a wide range of cancers, about 25% of whom were taking aspirin. Heterogeneity is large but, overall, aspirin is associated with increases in survival and reductions in metastatic spread and vascular complications of different cancers. It is important that evaluations of aspirin used as an adjunct cancer treatment are based upon all the available relevant evidence, and there appears to be a marked harmony between the effects of aspirin upon biological mechanisms and upon the clinical progress of cancer.     

Comparison of the developmental toxicity of aspirin in rabbits when administered throughout organogenesis or during sensitive windows of development

BACKGROUND: A review of the nonsteroidal anti‐inflammatory drug (NSAID) literature suggested occurrences of low‐level incidences of cardiovascular and midline defects in rabbit fetuses exposed in utero. Aspirin (acetylsalicylic acid, ASA) is a widely used NSAID that irreversibly inhibits cyclooxygenases (COXs) 1 and 2. ASA has been studied extensively in rats and has consistently increased low‐incidence cardiovascular malformations and defects in midline closure. The objectives of the current study were to comprehensively define the developmental toxicology profile of ASA in rabbits by using a dosing paradigm encompassing the period of organogenesis and to test the hypothesis that maternal gastrointestinal toxicity after repeated dose administrations hampers the detection of low‐incidence malformations with ASA in rabbits by limiting ASA administration to sensitive windows for cardiovascular development and midline closure. METHODS: ASA was administered to pregnant New Zealand White rabbits from gestation days (GDs) 7 to 19 at dose levels of 125, 250, and 350 mg/kg per day and as single doses of 500, 750, or 1000 mg/kg on GD 9, 10, or 11. Cesarean sections were performed on GD 29, and the fetuses were examined for external, visceral, and skeletal development. RESULTS: In the repeated dose study, maternal toxicity was exhibited in the 250‐ and 350‐mg/kg per day groups by mortality and decreased food consumption and body weight gain. In the single dose studies, maternal toxicity was exhibited at all doses by reductions in body weight gain and food consumption for 3 days after treatment. Fetal body weight was significantly reduced in the repeated dose study at 350 mg/kg per day. Fetal weights were not affected by single doses of ASA on GD 9, 10, or 11. There were no treatment‐related external, visceral, or skeletal malformations associated with ASA administration throughout organogenesis or with single doses administered during critical developmental windows. CONCLUSION: These findings supported previous work demonstrating that ASA is not teratogenic in rabbits, as opposed to rats, even when large doses are administered on single days during specific windows of development. Birth Defects Research (Part B) 68:38–46, 2003. © 2003 Wiley‐Liss, Inc.     

Use of aspirin in the prevention of colorectal cancer through TIGIT‐CD155 pathway

Colorectal cancer (CRC) is one of the most widespread malignant cancers, with a high incidence and mortality all over the world. Aspirin (ASA) otherwise known as acetylsalicylic acid, is a non‐steroidal anti‐inflammatory drug that has shown promising results in the prevention of chronic diseases, including several cancers. In previous studies, aspirin has been shown to reduce the incidence of CRC. Immune checkpoint blockade of T cell Ig and ITIM domain receptor (TIGIT) alone or combined with other immune checkpoint blockades moleculars has gained impressive results in the treatment of the melanoma and glioblastoma. Here, we found that TIGIT and Poliovirus receptor (PVR, CD155) are expressed in tumour cells; the TIGIT and CD155 protein expression in cancer tissue has been found to be significantly higher than that in the precancerous tissue. T cell Ig and ITIM domain receptor and CD226 were expressed in the lymphocytes near the tumour tissue and the adjacent tissues. Aspirin has been found to inhibit cancer cell viability and promote CRC cell apoptosis.Similarly, aspirin has also been found to increase pro‐apoptotic protein Bax's expression. We found that the expression of TIGIT decreased with an increase in the concentration of aspirin and that the suppression of TIGIT can affect the effect of aspirin on cell proliferation. In this paper, we found that aspirin attenuates cancer cell proliferation and induces CRC cells apoptosis by down‐regulating the expression of TIGIT, which provides new evidence for the application of aspirin in cancer treatment.     

From plant extract to molecular panacea: a commentary on Stone (1763) ‘An account of the success of the bark of the willow in the cure of the agues’

The application of aspirin-like drugs in modern medicine is very broad, encompassing the treatment of inflammation, pain and a variety of cardiovascular conditions. Although anecdotal accounts of willow bark extract as an anti-inflammatory drug have occurred since written records began (for example by Hippocrates), the first convincing demonstration of a potent anti-pyretic effect of willow bark containing salicylates was made by the English cleric Edward Stone in the late eighteenth century. Here, we discuss the route to optimizing and understanding the mechanism of action of anti-inflammatory drugs that have their origins in Stone''s seminal study, ‘An account of the success of the bark of the willow in the cure of agues’. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.     

Anti-inflammatory drugs promote polyspermic fertilization in sea urchins

Sea urchin eggs are known to release H₂O₂ during the cortical reaction at fertilization to help prevent polyspermy by inactivating excess sperm in the vicinity. This process resembles the peroxidatic killing of bacteria by phagocytic leukocytes during inflammation. Associated with these reactions in leukocytes, arachidonic acid is released from phospholipids and can be oxidized via the cyclooxygenase pathway to produce prostaglandins. Nonsteroidal anti-inflammatory drugs (NSAID) that are cyclooxygenase inhibitors in somatic cells were used to determine whether Arbacia punctulata and Strongylocentrotus purpuratus eggs use these processes to help prevent polyspermy. The potent cyclooxygenase inhibitor indomethacin causes a dose (10–100 μM) and sperm density dependent induction of polyspermy if added before the egg completes the cortical reaction. It does not retard elevation of the fertilization envelope and does not promote polyspermy by protecting sperm from peroxidatic inactivation by egg-derived H₂O₂. Other potent cyclooxygenase inhibitors, flufenamate and meclofenamate, also induce polyspermy at 10–60 μM. Aspirin, a weak cyclooxygenase inhibitor in somatic cells, does not cause polyspermy at 5 mM. These findings provide evidence that prostaglandins or other cyclooxygenase-derived metabolites may help assure monospermic fertilization in sea urchins.     

Platelet activating factor-induced aggregation of calf platelets: Apparent positive cooperativity in the kinetics and non competitive inhibition by diltiazem

Aggregation of calf platelets by platelet activating factor was characterized by a spectrophotometric method. The aggregation kinetics of both platelet-rich plasma and purified platelets showed concave up double-reciprocal plots and linear Hill plots withh > 1 (1.7 ± 02) consistent with positive cooperativity. Comparable values of maximum rates of aggregation(R) were obtained with platelet-rich plasma (0.25 ± 0.08) and purified platelets (0.28 ± 0.18) but the half-maximal saturation concentration (S_0.5) differed greatly between platelet-rich plasma (6 ± 3 nM) and purified platelets (0.28 ± 0.18 nM). An Arrhenius activation energy of 21 ±2 kcal/mol was found for aggregation of purified platelets. Diltiazem was inhibitory with half-maximal inhibitory concentration (I_0.5) of 4 M but the inhibition was not competitive. Diltiazem inhibited rates but not the extent of shape-change. The receptor-antagonist and sulphydryl reagent N-ethylmaleimide and the platelet antagonistic omega-3-fatty acid, 5,8,11,14,17-eicosa pentaenoic acid, inhibited both rates and extent of shape-change reactions and inhibited aggregation competitively (I_0.5 ∼ 5 M). Eicosa pentaenoic acid at > 25 M could abolish shape-change reactions and at 50 M served as an activator of platelets and the activation was enhanced by aspirin (1 mM). Although N-ethylmaleimide at > 20 M could also induce platelet activation it failed to induce aggregation and aspirin had no effect on the shape-change reactions induced by it.